The present invention relates to a collagen material comprising a laminate in which a collagen ultra-fine fibrous non-woven fabric-like multi-layer structure is sandwiched between non-fibrous collagen layers, a thread-like material containing said collagen material, and their production processes, as well as a medical material containing said collagen material, and particularly a medical alternative membrane comprised of said medical material.
Among the various materials used as medical materials, animal collagen has excellent bioaffinity and histocompatibility, low antigenicity, has the action of promoting host cell differentiation and growth, has a hemostatic action, and is completely broken down and absorbed in the body. Consequently, it has properties that are particularly suitable for use as a medical material. At present, animal collagen types I through XIX have been discovered, collagen types I through V are used in a variety of ways as medical materials. In particular, type I collagen, which is useful as an extracellular matrix, is used most commonly. These collagens are extracted and purified from the connective tissue of various organs such as skin, bone, cartilage, tendon, and viscus of animals such as cows, pigs, birds, kangaroos and so forth by acidic solubilization, alkaline solubilization, neutral solubilization and enzymatic solubilization. Extracted collagen used conventionally is one that has been broken down to monomers and oligomers at the molecular level, and is stored in the form of a powder or liquid. Since these extracted collagens are in a state in which collagen molecules are broken down to monomers and oligomers, when they come in contact with water, body fluids or blood, they form a sol extremely rapidly. Consequently, when using these collagens by molding as medical materials, they are either used by covering the surface of a synthetic polymer material such as Nylon or silicone with collagen to give the material a certain degree of strength during processing, or are used by subjecting the molded product of the extracted collagen to chemical crosslinking treatment using a crosslinking agent or to physical crosslinking treatment using radiation, electric beam, ultraviolet rays or heat in order to hold the shape of the material for a certain period of time in the case of applying to the body. In addition, although these extracted collagens may be used as thread for medical treatment by forming into the shape of a thread, wet spinning is used for its spinning.
However, in the case of a material in which collagen is combined with a synthetic polymer material, the synthetic polymer material remains in the body as a foreign object resulting in susceptibility to the occurrence of disorders such as granulation and inflammation, and this type of material cannot be applied to all cells and viscera. In addition, even if crosslinking treatment is performed on collagen materials, since there is hardly increase at all in the physical properties of the collagen material, and particularly tear strength, it was not possible to process this material for use as a medical material requiring suturing. In addition, when a crosslinking agent such as glutaraldehyde or epoxy is used, not only does the toxicity of the crosslinking agent on the body become a problem, but there is also the disadvantage of the biochemical properties inherently possessed by collagen, and particularly promotional effects on cell growth, being lost. In addition, in the case of physical crosslinking treatment, the crosslinking rate is unstable and it is unable to give adequate physical properties to the collagen material. In addition, it has also been difficult to perform crosslinking treatment so that the absorption rate in the body can be controlled. On the other hand, since spun collagen does not have sufficient strength, it is not adequate for use as suture.
On the other hand, although it is necessary to close by resuturing an opened endocranium, pericardium, pleura, peritoneum or serous membrane when closing a surgical wound after performing surgery on the brain or various viscera for the treatment of various diseases or trauma, there are many cases in which a missing portion forms in the membrane that prevents a surgical wound from being completely closed due to the formation of a shortened portion depending on the length of the suture or the membrane being partially severed. If such a missing portion is left uncorrected, the viscera such as the brain, heart, lung, and intestine may herniate from the area where the membrane is missing resulting in a serious disorder, or water or air may escape from the viscera or area around the viscera preventing the surgical wound from healing. In addition, since the viscera may adhere to surrounding tissues, the tissue may be damaged thereby preventing the obtaining of a favorable prognosis. Consequently, freeze-dried human endocranium removed from cadavers or porous elastic polytetrafluoroethylene film (EPTFE) (Tissue Goretex, trade name), polypropylene mesh, Teflon sheet or Dacron sheet and so forth are used as alternative medical membranes that can be used as fillers for these missing portions. In addition, a copolymer of lactic acid and xcex5-caprolactone (50:50) is currently being developed. In addition, methods involving the use of the patient""s own fascia lata or the patient""s own pericardium, skin or muscle and so forth are also performed as a last resort.
However, with respect to the use of human endocranium, adhesion occurs between the filled human endocranium and brain parenchymal tissue. Not only does this have the risk of causing epileptic attacks following surgery, there is also the ethical problem of obtaining specimens from human cadavers as well as the problem of the supply being extremely limited. More recently, the occurrence of Creutzfeldt-Jakob Disease (CJD) caused by transplanted endocranium has been reported in patients receiving endocranial transplants (J. Neurosurgery, 21(2): 167-170, 1993). In Japan, human endocranium is currently not used. In addition, since EPTFE materials and so forth are not broken down in the body but rather remain as foreign objects, they easily cause infection or, when in contact with body tissue, end up causing fatty degeneration of tissue cells and so forth, and are known to frequently cause post-operative complications. Copolymers of lactic acid and xcex5-caprolactone are degradable in the body. Although they gradually are broken down after being applied to the body, a long period of time on the order of nearly two years is required for them to be completely broken down and absorbed. Consequently, they also remain in the body for a short time as foreign objects, cause inflammation in tissue during the degradation process and form granuloma. Since this copolymer uses the (L) form of lactic acid as its monomer, lactic acid may crystallize in the copolymer causing inflammation. Moreover, both EPTFE and copolymer of lactic acid and xcex5-caprolactone do not have the action of promoting regeneration of biomembranes. In addition, methods using the patient""s own fascia lata and so forth place a significant burden on both the patient and physician.
Although materials such as the above-mentioned EPTFE, polypropylene mesh (Marlex), human dried endocranium and glutaraldehyde (GA)-treated bovine pericardium have been used in the past as pericardium fillers, EPTFE and human dried pericardium have the disadvantages described above. In addition, polypropylene mesh causes strong adhesion between itself and the heart. Since GA-treated bovine pericardium remains in the body without being absorbed or broken down, it causes deterioration due to mineral deposition, and complications due to interstitial pneumonia caused by an immune reaction to the bovine pericardium have also been observed.
In addition, although polyglycolic acid non-woven fabric and bovine pericardium have been used as a pleural filler or for an auto-suture to reduce the escape of air from the surgical site following lung surgery, polyglycolic acid causes strong adhesion and because it is not transparent, it is difficult to be used for an auto-suture. In addition, bovine pericardium has the disadvantages previously described.
For these reasons, a need has arisen for the development of a collagen material that uses collagen for its raw material without combining the use of a synthetic polymer material, possesses physical properties to an extent that allows suturing while still maintaining the biochemical properties inherently possessed by collagen, and retains its shape for a certain amount of time even after application to the body; its production process; and, a medical material on which it is based, examples of which include a peripheral neural tube, artificial spine, artificial esophagus, artificial trachea, artificial blood vessel, artificial valve or artificial alternative medical membranes such as artificial endocranium, artificial ligaments, artificial tendons, surgical sutures, surgical fillers, surgical reinforcement, wound protecting materials, artificial skin and artificial cornea. In particular, there has arisen a strong need in the clinical setting for the development of various types of medical materials that can be used as alternative medical membranes which present no ethical problems, are in stable supply, prevent adhesion of the surgical wound following surgery after being applied to the body, have no risk of infection, do not cause tissue degeneration, allow control of the rate of degradation following application, and have an action that promotes regeneration of biomembranes, especially endocranium, pericardium, pleura, peritoneum or serous membrane.
As a result of earnest research in order to solve the above-mentioned problems, the inventors of the present invention found that a collagen material comprising a laminate in which a collagen ultra-fine fibrous non-woven fabric-like multi-layer structure is sandwiched between non-fibrous collagen layers has excellent properties as a medical material as well as physical properties that allow suturing, thereby leading to completion of the present invention. Namely, the present invention relates to a collagen material comprising a laminate in which a collagen ultra-fine fibrous non-woven fabric-like multi-layer structure is sandwiched between non-fibrous collagen layers. In addition, the present invention relates to a production process of the above-mentioned collagen material comprising freezing a collagen solution layer; freeze-drying to form a fine fibrous collagen layer; compressing; repeating a process consisting of immersing in a collagen solution and air-drying; followed by subjecting to crosslinking treatment. Moreover, the present invention relates to a thread-like material containing a collagen material comprising a laminate in which a collagen ultra-fine fibrous non-woven fabric-like multi-layer structure is sandwiched between non-fibrous collagen layers; and, a production process of the above-mentioned thread-like material comprising wet-spinning a collagen solution to obtain collagen threads; freezing the collagen threads; freeze-drying; compressing the collagen threads; repeating a process consisting of immersing in collagen solution and air-drying; followed by subjecting to crosslinking treatment. Moreover, the present invention relates to a medical material containing a collagen material comprising a laminate in which a collagen ultra-fine fibrous non-woven fabric-like multi-layer structure is sandwiched between non-fibrous collagen layers, an alternative medical membrane comprised of said medical material, and particularly an alternative medical membrane having a crosslinked gelatin gel layer or hyaluronic acid layer on one or both sides.